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Y. Saunthararajah et al.
thus, if a chemical modification produces a high oxygen affinity hemoglobin molecule, there is a necessary play off between decreased oxygen supply from increased oxygen affinity of hemoglobin versus increased oxygen supply from less HbS polymerization/higher total hemoglobin. This balancing act is discussed in more detail in the sec- tion ‘Lessons learned so far’ below. Ultimately, however, rigorous clinical evaluation is key,5,118 and clinical evalua- tion has started or is underway for a number of candidate drugs that exploit these principles:
Small molecules to convert hemoglobin to methemoglobin
The earliest clinical effort in this field evaluated the con- version of hemoglobin to methemoglobin following the administration of sodium nitrite or para-amino-proprio- phenone (PAPP) to five patients.119 Both agents were able to increase methemoglobin. Methemoglobin levels of >20% (but not less) produced by sodium nitrite extended RBC survival as measured by chromium-labeling. The methemoglobinemia itself was apparently well-tolerated, but there was no evidence of any clinical benefit. Instead, there were significant side-effects from the administered drugs.119
Interestingly, higher methemoglobin levels produced by PAPP did not extend RBC survival, possibly because PAPP was directly hemolytic.
Small molecules to convert hemoglobin to carboxyhemoglobin
Carbon monoxide can be used to convert hemoglobin to carboxyhemoglobin. Infusion of free pegylated carboxyhe- moglobin (MP4CO), as a hemoglobin-based carbon monoxide carrier, was evaluated in a phase I study.120 In an abstract description of results in 18 patients, the maximum increase in carboxyhemoglobin was to 2%, which returned to pre-dosing levels within 8 h of completion of the MP4CO infusion. There was no significant increase in total hemoglobin. No further studies have been reported.
Small molecules that delay HbS polymerization by unclear mechanisms
Niprisan (Nix-0699) and related small molecules (SCD- 101) are plant-derived molecules that have been found to delay polymerization of deoxygenated HbS, but by unclear mechanisms.121 SCD-101 has been evaluated in a phase IB clinical trial in 26 SCD patients. There were no major adverse events attributed to the drug taken for 28 days, and it appeared to decrease chronic pain and fatigue at higher doses. However, there were no laboratory data providing evidence of decreased hemolysis or increased total hemoglobin, although analysis of peripheral smears suggested improvements in RBC shape.122
Small molecules to increase hemoglobin oxygen affinity
Specific small molecule aldehydes have been found to form reversible Schiff base linkages with the N-terminal amino group of hemoglobin a chains to lock in the high oxygen affinity R conformation, and the polyaromatic adldehyde GBT440 (voxeletor) has been developed through to phase III clinical trial evaluation. In phase I/II randomized, double-blind, placebo-controlled evaluation in SCD patients, some of whom were receiving concur- rent therapy with hydroxyurea, there were increases in total hemoglobin of ≥1 g/dL in six of 12 patients who received the drug for 90 days or more.123 There were con- current decreases in markers of hemolysis (lactate dehy-
drogenase, total bilirubin). There were no significant adverse events attributed to study drug. Oxygen delivery was evaluated by measurement of oxygen consumption during cardiopulmonary exercise testing, erythropoietin levels, resting heart rate and heart rate during peak exer- cise, and these parameters did not suggest decreased oxygen delivery to tissues.123 A subsequent double-blind, randomized, placebo-controlled phase III clinical trial evaluated two different doses of the study drug (900 and 1500 mg per day) in 274 SCD patients, two-thirds of whom remained on stable doses of hydroxyurea initiat- ed well before study enrollment.124 A hemoglobin response, defined as an increase from baseline of >1 g/dL at week 24, occurred in 51% of the patients on the 1500 mg dose, 33% on the 900 mg dose, and 7% on placebo, in intention-to-treat analyses. There were also improve- ments in biomarkers of hemolysis. The frequency of vaso-occlusive crises did not differ between the treat- ment arms. Breakdown of vaso-occlusive crisis frequen- cy according to whether or not the patients were taking hydroxyurea was not reported. Erythropoietin levels (as a surrogate for oxygen delivery) as well as grade 3 and serious adverse events were similar between the treat- ment arms.124
Chemical modification of HbS – lessons learned so far and open questions
Balancing acts
The clinical trial results with GBT440 thus illustrate that chemical modification of hemoglobin to increase its oxy- gen affinity (promote the hemoglobin R conformation) can indeed significantly decrease hemolysis and signifi- cantly increase total hemoglobin. The hope and goal is that higher hemoglobin increases oxygen supply by amounts that exceed any decrease in oxygen supply from the higher oxygen affinity of the modified hemoglobin molecule,5,118 as per the equation:
Oxygen Supply = Blood Flow (mL blood/100 g tissue/min) x Arterial Oxygen Saturation (%)
x Total Hemoglobin (g/dL).125
Thus, increasing total hemoglobin increases oxygen
supply, but chemical modification of some of these hemo- globin molecules to increase oxygen affinity decreases effective arterial oxygen saturation and oxygen supply. Some tissues, e.g., the brain, have limited capacity to increase the ‘blood flow’ component in the equation, and hence, are particularly dependent on the ‘arterial oxygen saturation’ x ‘total hemoglobin’ components, as extensive- ly modeled recently.118,125 Underscoring this point, most silent cerebral infarctions in SCD children have been found to be caused by disruption to oxygen supply that is not caused by large vessel vasculopathy, implying anemia and/or blood oxygen saturation are critical drivers of this hypoxic damage.126-128
Even the ‘blood flow’ component of the equation is a balancing act in SCD patients: whole blood viscosity is a key determinant of blood flow; less HbS polymerization, by increasing (improving) RBC deformability, can decrease whole blood viscosity and thus increase blood flow. On the other hand, higher total hemoglobin/hemat- ocrit can increase blood viscosity which can decrease blood flow, even with hematocrits in an anemia range, because of the contribution of baseline low RBC deforma- bility of SCD to viscosity. This blood flow calculus needs
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haematologica | 2019; 104(9)